Many biologically active substances such as certain low-molecular pharmaceutical agents, peptides, nucleic acids, vaccines or hormones are preferably administered in parenteral fashion.
The reason in many cases is a strong mechanical, chemical or enzymatic degradation in the stomach, intestines or liver of patients after oral administration, or limited bioavailability due to inadequate resorption from the gastrointestinal tract.
One example of a strongly degradation-prone agent is N-0923 (S(−)-2-(N-propyl-N-2-thienylerhyl-amino)-5-hyroxytetralin), a dopamine D2 agonist for treating Parkinson's disease. Because of a distinct first-pass effect the bioavailability after oral administration is as low as about 0.5% (Swart and Zeeuw, Pharmazie 47 (1992), ruling out oral forms of N-0923 administration.
Other examples of agents with inadequate gastrointestinal absorption include peptides, proteins, enzymes or nucleic acids which when administered orally are usually not absorbed or only to a therapeutically irrelevant extent.
There is a substantial demand for these active agents in the form of parentally applicable medications. Yet many agents have a short half-time value even when injected since they are rapidly eliminated from the body.
Here again, N-0923 is a good example. In tests with animals, the half-time value of intravenously injected aqueous N-0923 solutions was 52 minutes (Walters et al, J Pharmac Sci 83 (1994) 758), and after subcutaneous administration it was 60–70 minutes (Belluzzi, Movement Disorders, 9.2 (1994) 147), which in the case of an extended therapy would require administration at a frequency altogether unacceptable to the patient.
It is the elimination half-time value especially of many peptides and enzymes that is very limited. For example, insulin injected in an aqueous solution has a half-time value of about 6 minutes, proinsulin C-peptide about 30 minutes.
The situation is similar with the pharmacokinetics of nucleic acids, oligonucleotides or nucleoside analogues. For example, the 5-fluorouracil used in cancer treatment has a half-time value of only 10–20 minutes, it is ineffective when taken orally and it must be administered by continuous infusion.
Consequently, for substances of this type with low oral bioavailability and rapid elimination there is a great demand for systemic medications that significantly reduce the frequency or duration of the therapeutic administration.
One method of retarding injected agents involves the administration in the form of suspensions. When substances are suspended in aqueous solutions, the active agent is precipitated for instance with metal ions or charged substances, with the agent reversibly bound to the ion.
Examples thereof include aqueous zinc-insulin or zinc-insulin-protamine suspensions that have been in use since the 1930s. The ratio between bound and free agent components determines the retention effect to be expected. One example of an insulin-zinc crystal suspension of this type is described in EP-A-0 025 868.
However, developing depot-type medicines of that nature is a difficult matter and depends largely on the characteristics and individual physiochemical properties of the agent concerned. It follows that the results obtained with an agent such as insulin are not or at least not easily reproducible with other agents.
Oily suspensions of aqueous agents have also been around for some time. Their drawback, however, is that the suspensions are viscous to a point where they either would not flow through standard cannulas or they are unstable, so that even after brief storage they form sedimentations from which the suspensions can no longer be fully extracted.
One example for producing stable, injectable oily peptide preparations is described in OS DE 2,306.075. As a first step, the peptides are mixed with a fatty acid aluminum salt and the resulting adsorbate is suspended in oil or the peptides are suspended in an oily gel that contains fatty acid aluminum salt as the gel-forming agent. The drawback of the formulation described, however, is that the aluminum contained therein is a toxic metal which, especially in the case of repeated administration, can create a major problem from the toxicology point of view. Moreover, the release of active agents from gels is difficult to control, the application is often unpleasant for the patient and in the event of incorrect injections there is a significant risk of systemic side effects.
U.S. Pat. No. 5,013,713 describes injectable peptide preparations. For retardation it proposes the conversion of the peptides into low-solubility salts which are then to be suspended in an oily vehicle. This is preferably followed by the addition of dehydrating reagents such as magnesium stearate or fatty acid metal salts that lead to gel formation. The drawback of that method lies in the fact that the pharmacokinetic and pharmacologic properties of the metal salts concerned are difficult to predict. Moreover, the solid particles in the proposed pharmaceutical formulations tend to be subject to aggregation, sedimentation and the formation of insoluble deposits.
This invention was therefore aimed at providing a pharmaceutical formulation that is stable, consists of as few components as possible and is capable of serving as an injectable depository vehicle for a large variety of active agents.
The formulation had to continuously release the active agents over a time span of at least 12 and preferably more than 24 hours, it had to have an adequate shelf life and it had to be highly biocompatible, nontoxic, completely biodegradable and easy to produce.
According to the invention, this objective has been achieved by means of an injectable pharmaceutical formulation comprising a pharmacologically active agent in its solid phase, a liquid vehicle essentially consisting of polyol fatty acid esters with a high esterification level and a wetting agent essentially consisting of polyol fatty acid esters predominantly in the form of monoesters.
Surprisingly, it is possible with this very simple pharmaceutical formulation to obtain a therapeutically meaningful pharmacon plasma level over as many as 48 hours. Yet the composition per this invention is astonishingly simple, cost-effective in its production, stable when stored, thermally sterilizable and easily resuspended.
As another particular advantage, the above-mentioned composition contains very few, well-defined, well-tolerated and biodegradable additives.
Another advantage of this invention is its suitability for a wide range of applications. The pharmaceutical preparation according to the invention lends itself to the administration of numerous different active agents. Individualized selection of the injection volume, the application intervals and the pharmacon concentration of the formulations per the invention permits the easy adaptation of the dosage to the requirements, symptoms and condition of each patient.
Compared to slow-acting substances deposited in the body for releasing pharmacons i.e. active agents over 1, 3 or even 6 months, the pharmaceutical preparations according to the invention offer the advantage of better controllability. For example, with some patients it is desirable to see the biocatalyst removed from the body over a specific time. This is important especially in the case therapeutics with a narrow therapeutic index.